Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma.

PURPOSE: To evaluate the safety and efficacy of fludarabine plus rituximab in treatment-naive or relapsed patients with low-grade and/or follicular non-Hodgkin's lymphoma. PATIENTS AND METHODS: This was an open-label, single-arm, single-center phase II study enrolling 40 patients. During the first week of the study, patients received two infusions of rituximab 375 mg/m2 administered 4 days apart. Seventy-two hours after the second infusion of rituximab, patients received the first of six cycles of fludarabine chemotherapy (25 mg/m2/d for 5 days on a 28-day cycle). Single infusions of rituximab were administered 72 hours before the second, fourth, and sixth cycles of fludarabine, and two infusions of rituximab were given 4 weeks after the last cycle of fludarabine. Treatment duration was 26 weeks. RESULTS: An overall response rate of 90% (80% complete response rate) was achieved in the intent-to-treat population. Similar response rates were seen in treatment-naive and previously treated patients. The median duration of response has not been reached at 40+ months. The median follow-up time in this study is 44 months (range, 15 to 66 months). In patients positive for the 14;18 translocation in blood and/or marrow at enrollment, molecular remission was achieved in 88% of cases, with patients remaining negative for up to 4 years to date. Hematologic toxicity was manageable, and except for a 15% incidence of herpes simplex/zoster infections, infectious complications were rare. Nonhematologic toxicities were minimal. CONCLUSION: Rituximab plus fludarabine was well tolerated and associated with an excellent complete response rate, including molecular remissions, in patients with low-grade or follicular lymphoma.

HLA-DR antigen-negative acute myeloid leukemia.

Human leukocyte antigen (HLA) Class II antigens are variably expressed on acute myeloid leukemia (AML) blasts. The biological and clinical significance of HLA Class II antigen expression by AML cells is not known. Therefore, we sought to characterize cases of AML without detectable HLA-DR expression. Samples from 248 consecutive adult AML patients were immunophenotyped by multiparameter flow cytometry at diagnosis. HLA-DR antigens were not detected on AML cells from 43 patients, including 20 with acute promyelocytic leukemia (APL), and 23 with other subtypes of AML. All APL cases had t(15;17), but there were no characteristic chromosome abnormalities in non-APL cases. No direct expression of other antigens was identified in HLA-DR-negative APL and non-APL cases. Interestingly, cells from three HLA-DR-negative non-APL patients had similar morphology to that of the hypogranular variant of APL. This morphology, however, was not present in any HLA-DR-positive AML cases. Treatment response was similar in the 23 HLA-DR-negative non-APL and the 205 HLA-DR-positive patients. Finally, relapse was infrequently associated with changes in HLA-DR antigen expression, as the HLA-DR antigen was lost at relapse in only 4% of HLA-DR-positive cases, and was gained at relapse in only 17% of HLA-DR-negative cases. We conclude that HLA-DR-negative AML includes approximately equal numbers of APL and non-APL cases, and that the morphology of HLA-DR-negative non-APL cases can mimic the hypogranular variant of APL. The diagnosis of APL cannot be based on morphology and lack of HLA-DR antigen expression; rather, it requires cytogenetic or molecular confirmation.

Nurses' attitudes toward clinical trials at a comprehensive cancer center.

PURPOSE/OBJECTIVES: To identify nurses' attitudes and beliefs toward cancer clinical trials and their perceptions about factors influencing patients' participation in these trials. DESIGN: Descriptive. SETTING: National Cancer Institute-designated comprehensive cancer center. SAMPLE: 417 nurses employed at the cancer center were surveyed; 250 (60%) subjects responded. METHODS: 59-item questionnaire. MAIN RESEARCH VARIABLES: Nurses' attitudes toward clinical trials and perceptions of patient understanding of and influences on participation in clinical trials. FINDINGS: 96% of nurses reported that participation in clinical trials is important to improving standards of care; only 56% believed that patients should be encouraged to participate in trials if they had cancer. In multiple regression analyses, older age and being a research nurse were significant predictors of positive attitudes toward clinical trials. Work setting also was a significant predictor of nurses' perceptions of patients' understanding of treatment. Overall, nurses reported that an investigational therapy should have at least a 50% chance of success prior to being offered to patients. CONCLUSIONS: Nurses generally reported that clinical trials are important to improve standards of care; however, attitudes concerning patient participation in clinical trials and perceptions of patient understanding differed by work setting. Nurses have high expectations regarding the benefits of investigational therapy. IMPLICATIONS FOR NURSING PRACTICE: Nurses play a critical role in the care of participants in cancer clinical trials. Targeted interventions that involve nurses to enhance appropriate patient accrual, patient understanding, and patient decision making should result in improved patient care in centers conducting clinical trials.

Validation of a new classification system for curatively resected colorectal adenocarcinoma.

BACKGROUND: The parameters within which colorectal adenocarcinoma is currently staged are often insufficient for decisions regarding therapy after potentially curative surgery. Consequently, oncologists make frequent use of additional prognostic indicators when assessing individual prognosis and selecting patients for adjuvant systemic treatment. Follow-up programs are generally uniform for all patients, regardless of disease stage and prognosis. As a result, patients with a favorable prognosis are needlessly subjected to stressful, costly follow-up too early and too frequently. This study was conducted to validate a new classification system that is a superior predictor of individual prognosis following curative surgery and may serve as a guide for personalized, cost-effective postoperative management and follow-up. METHODS: A total of 231 American colorectal carcinoma patients who underwent curative resection were retrospectively staged according to a new classification (containing 4 stage-groups) for curatively resected colorectal adenocarcinoma. This classification is based on statistical analysis of the impact on prognosis of numerous characteristics of 363 consecutive Israeli colorectal carcinoma patients who underwent curative resection. All the patients in both cohorts had had surgery at least 5 years previously. The new classification is based on three histologic variables (venous invasion, depth of primary tumor penetration, and regional lymph node status) and a scoring system that correlates higher numeric score with worse prognosis. In both cohorts, the new classification was compared with the Dukes, Astler-Coller, and TNM staging systems for patient distribution and survival (both disease free and cancer-related survival). RESULTS: In both cohorts, the 4 stage-groups of the new classification differed significantly in both the rate of and the time to first recurrence and cancer-related death, with progression from Group 4 to Group 1. Groups of high risk lymph node negative patients were defined, and lymph node positive patients were subdivided according to prognosis. It is suggested that, by using this new classification as a guide, selection for adjuvant systemic treatment may be refined, and postoperative follow-up may be personalized and therefore more cost-effective. CONCLUSIONS: The new classification for curatively resected colorectal adenocarcinoma, based on an analysis of the Israeli cohort and validated in the American cohort, is superior to the Dukes, Astler-Coller, and TNM staging systems as a predictor of individual prognosis, most probably because it incorporates the microscopic forerunner of distant, hematogenous spread (i.e., venous invasion) with the locoregional parameters of extent of disease (i.e., T and N values). It is suggested that the new classification may serve as a guide for more refined selection of patients for adjuvant systemic treatment and for individualized and more cost-effective postoperative follow-up. The new classification is simple and easy to use, requires no sophisticated equipment or tests, and can be applied in any health care system worldwide.

New approach to the substaging of node-positive colorectal adenocarcinoma.

BACKGROUND: Future developments in adjuvant modalities may require substaging of node-positive colorectal adenocarcinoma that is accurately indicative of individual prognoses, upon which therapeutic decisions (e.g., choice of agents and intensity of treatment) may be based. This study compares substaging of node-positive colorectal cancer by venous invasion with substaging by three currently used methods, with respect to the ability of each method to define patient subsets that differ significantly in both disease-free and cancer-related survival rates. METHODS: A total of 171 patients with node-positive colorectal cancer, who had undergone potentially curative resection at least 5 years earlier, were retrospectively substaged by the tumor, node, metastasis (TNM) N1/N2, Astler-Coller C1/C2, Gastrointestinal Tumor Study Group (GITSG) C1/C2, and venous invasion (positive/negative) methods. Disease-free and cancer-related survival curves were calculated (by the Kaplan-Meier method) and compared for statistical significance (using the log-rank test). RESULTS: The separation of disease-free and cancer-related survival curves using the four methods of substaging node-positive colorectal cancer was as follows: TNM, P = .16 (not significant) and P = .12 (not significant); Astler-Coller, P < .01 and P = .006; GITSG, P = .067 (not significant) and P = .03; venous invasion, P = .016 and P = .007, respectively. CONCLUSIONS: Numerical substaging of node-positive colorectal cancer (TNM and GITSG methods) is an inferior predictor of prognosis, compared with substaging by the T value (Astler-Coller) or venous invasion methods. We think that the latter method is the method of choice, because it separates patients who have only lymphatic metastasis from patients who display microscopic hematogenous spread as well. This separation obviously has biological/oncological significance, and it may have practical therapeutic implications in the future.

Phase I and pharmacokinetic study of weekly 5-fluorouracil administered with granulocyte-macrophage colony-stimulating factor and high-dose leucovorin: a potential role for growth factor as mucosal protectant.

Diarrhea is dose-limiting with weekly 5-fluorouracil (5-FU) plus high-dose leucovorin (LV). Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been associated with a decrease in chemotherapy-associated mucosal toxicity. This study was conducted to determine the maximum tolerated dose (MTD) of weekly 5-FU when administered with GM-CSF and high-dose LV. Patients were treated with intravenous LV 500 mg/m2 plus 5-FU weekly for six doses followed by a 2-week rest. GM-CSF 250 mg/m2 was administered subcutaneously 5 days each week. Cohorts were treated with 5-FU at 600, 700, and 800 mg/m2 weekly. Twenty-nine patients were treated. The MTD of 5-FU in this schedule was 700 mg/m2/week, with diarrhea dose-limiting. 5-FU delivered dose intensity at the MTD was 424 +/- 23.7 mg/m2/week, including rest periods. 5-FU and LV pharmacokinetics were not altered by concurrent treatment with GM-CSF. In a weekly schedule with high-dose LV and GM-CSF, the MTD of 5-FU and 5-FU delivered dose intensity were higher than previously reported with 5-FU and LV administered without GM-CSF.

Prolonged disease-free survival by maintenance chemotherapy among patients with recurrent platinum-sensitive ovarian cancer.

OBJECTIVE: The aim of this study was to determine the potential benefit and complications of prolonged salvage and maintenance chemotherapy among patients with recurrent epithelial ovarian cancer who achieve response to salvage chemotherapy. METHODS: Patients with recurrent platinum-sensitive epithelial ovarian cancer who were treated between 1982 and 1996 and achieved complete response to platinum-based salvage chemotherapy were offered prolonged (1 year) monthly salvage followed by maintenance (every 8 weeks) chemotherapy. Patients who accepted such treatment (n = 16) were compared to those who refused and discontinued therapy (n = 11) with regard to overall survival from time of initial diagnosis and overall and disease-free survival from time of recurrence. Chemotherapy-related toxicity in the study group was recorded. Survival curves were constructed according to the Kaplan and Meier method and survival curves were compared using the log-rank test. RESULTS: Patients in the study and control groups were similar with regard to age, stage, histology, grade, performance status, primary cytoreductive surgery, type of primary and salvage chemotherapy, and method of assessment of tumor response. The study group had a significantly longer disease-free interval from date of recurrence than the control group (median: 35.0 versus 6.0 months, respectively, P = 0.001). The study group had longer overall survival from date of recurrence than the control group. However, the difference did not achieve statistical significance (median: 119 versus 90 months, respectively, P = 0.056). There was no significant difference between the study group and the control group as to survival from date of initial diagnosis (median: 157 versus 124 months, respectively, P = 0.28). Chemotherapy-related toxicity was minimal. CONCLUSIONS: Prolonged salvage and maintenance chemotherapy is a safe method of treatment that may extend disease-free interval among patients with platinum-sensitive recurrent epithelial ovarian cancer who achieve response to salvage chemotherapy. These preliminary results need to be confirmed by a larger prospective randomized trial.

Prognostic factors in extraovarian primary peritoneal carcinoma.

OBJECTIVE: To determine the pathological, clinical, and therapeutic factors which had prognostic significance in women with extraovarian primary peritoneal carcinoma (EOPPC). METHODS: A retrospective, clinicopathologic study was conducted of 75 women diagnosed with EOPPC. Diagnosis and assessment of prognostic pathological factors were based on the Gynecologic Oncology Group (GOG) criteria. Univariate and multivariate analyses were used to assess the following factors for their effect on overall survival: age, parity, presenting symptoms and signs, ascites, CA 125 level, history of oophorectomy, maximum ovarian dimension, histologic type, architectural and nuclear grades, number of mitosis and psammoma bodies, depth of ovarian invasion, estrogen and progesterone receptors (positive, negative), p53 overexpression (present, absent), performance status (GOG criteria), stage (FIGO criteria for ovarian cancer), debulking surgery (optimal versus suboptimal), first-line chemotherapy (platin-based without paclitaxel versus platin/paclitaxel), secondary cytoreduction, and second-line chemotherapy (paclitaxel-based versus no paclitaxel). RESULTS: The median overall survival of all patients was 23.5 months (95% CI 18.6, 39.8 months). The 5-year survival was 26.5% (SE 6.7%). p53 overexpression and estrogen and progesterone receptor positivity were demonstrated in 42.4, 50.0, and 6.3%, respectively. In univariate analysis, performance status, primary debulking surgery, stage, and age were significant on overall survival (P < 0.001, <0. 001, 0.004, and 0.012, respectively). In multivariate analysis, only performance status (P < 0.001) and primary debulking surgery (P = 0. 03) were independent prognostic factors. Conclusions. Overall survival in women with EOPPC is affected significantly by performance status and primary debulking surgery as independent variables. To improve survival, efforts should be made to achieve optimal tumor cytoreduction at primary surgery.

Correlation between extreme drug resistance assay and response to primary paclitaxel and cisplatin in patients with epithelial ovarian cancer.

OBJECTIVE: The extreme drug resistance (EDR) assay has been correlated with failure of response to chemotherapy in greater than 99% of patients. The goal of this study is to correlate the results of the EDR assay to response to first-line paclitaxel/cisplatin among patients with epithelial ovarian cancer. METHODS: Seventy-five of 100 patients with epithelial ovarian cancer for whom EDR assay was performed were treated with weekly induction cisplatin (1 mg/kg body wt) x 4, followed by monthly paclitaxel (135 mg/m2) and cisplatin (75 mg/m2) x 6 and were evaluable for correlation of response to chemotherapy and EDR assay. Specimens for EDR assay were obtained at primary surgery and the EDR assay was performed by Oncotech, Inc. Response to chemotherapy was correlated to EDR assay results regarding paclitaxel and cisplatin. RESULTS: Among 75 evaluable patients, the prevalence of EDR to paclitaxel was 20.0% (n = 15) and to cisplatin it was 2.7% (n = 2). Only 1 patient (1.3%) exhibited EDR to both paclitaxel and cisplatin. Surgical assessment of response was performed in 42 patients; 33 patients were clinically evaluable. The overall response rate was 85.3%. The overall response rate for patients whose tumors demonstrated no EDR to either paclitaxel or cisplatin did not differ significantly from that for patients whose tumors demonstrated EDR to at least one of these two drugs (86.4% versus 81.3%, respectively, P = 0.692). Similarly, the complete surgical response rate for both groups did not differ significantly (25.4% versus 12.5%, respectively, P = 0. 34). A single patient whose tumor exhibited EDR to both paclitaxel and cisplatin had tumor progression. The sensitivity, specificity, positive predictive value, and negative predictive value of the EDR assay were 79.6, 27.0, 86.0, and 19.0%, respectively. CONCLUSIONS: EDR to paclitaxel does not preclude response to the combination of paclitaxel and cisplatin as primary therapy for patients with epithelial ovarian cancer. The role of the EDR assay in the primary management of patients with epithelial ovarian cancer remains to be determined.

Importance of lymph node metastases in primary peritoneal carcinoma.

BACKGROUND AND OBJECTIVES: The incidence and significance of lymph node involvement in patients with primary peritoneal adenocarcinoma (PPA) are unknown. The aim of the current study is to report on the incidence and significance of clinically or surgically detectable lymphadenopathy in women with PPA. METHODS: The study is a retrospective clinical review of patients with the confirmed diagnosis of PPA treated at Roswell Park Cancer Institute between 1982 and 1996. Patients with clinically or surgically detectable lymphadenopathy confirmed on histologic examination to be secondary to metastases from PPA were identified and compared to patients with negative lymph nodes with regard to clinicopathologic characteristics, treatment, response to treatment, and survival. RESULTS: Seventy-two patients with PPA were identified. Pelvic and periaortic lymph node biopsies or sampling were performed in 35% of the patients. In 8/72 patients (11%), lymphadenopathy was one of the presenting clinical or surgical findings. The clinicopathologic features, treatment, response to first-line chemotherapy, and estimated median overall survival were not different in patients with or without lymph node involvement (71.4% vs. 69.7%, P = 1.0, and 21.5 vs. 23.5 months, P = 0.14). CONCLUSIONS: Lymph node involvement is not an infrequent occurrence in patients with PPA and does not seem to be of adverse prognostic significance.

Improvements in pelvic exenteration: factors responsible for reducing morbidity and mortality.

BACKGROUND: Since pelvic exenteration for the treatment of recurrent gynecologic malignancy first was described, reported rates of morbidity and mortality have declined steadily. However, the factors responsible for this decline have never been clearly delineated. METHODS: We reviewed the charts of 154 patients who underwent pelvic exenteration for gynecologic malignancy between 1954 and 1994. Charts were abstracted for details of the surgical procedure, pathologic findings, postoperative management, short- and long-term complications, time to recurrence, and overall survival. RESULTS: Seventy-two patients (47%) experienced 95 identifiable postoperative complications, resulting in death in 22 patients (14%). The rate of infectious complications declined to a statistically significant degree between the first two decades and latter two decades of the study (odds ratio [OR] 0.28. 95% CI 0.11-0.69). The use of routine prophylactic antibiotics was associated with this decline in infectious complications (OR 0.25, 95% CI 0.07-0.83). The use of preoperative subcutaneous heparin was associated with a reduction in thrombotic complications from 5 of 100 patients to 0 of 54 patients (P = .11), as well as a significant reduction in overall risk of complications (OR 0.53, 95% CI 0.33-0.85) and risk of postoperative mortality (OR 0.19, 95% CI 0.05-0.80). There was a significant reduction in overall risk of postoperative complications with both intensive care unit monitoring postoperatively (OR 0.65, 95% CI 0.43-0.99) and routine postoperative monitoring with a pulmonary artery catheter (OR 0.61, 95% CI 0.38-0.98). CONCLUSIONS: Routine use of prophylactic antibiotics, prophylactic subcutaneous heparin, and intensive postoperative monitoring appear to have reduced morbidity from pelvic exenteration.

Expression and function of the megakaryocyte growth and development factor receptor in acute myeloid leukemia blasts.

The receptor for megakaryocyte growth and development factor (MGDF), also known as thrombopoietin, has recently been cloned. MGDF stimulates platelet production and maturation both in vitro and in vivo. MGDF may thus have a role in attenuating the thrombocytopenia associated with acute myeloid leukemia (AML) and its therapy. However, there is concern that MGDF might induce AML blast proliferation and thereby increase the risk of treatment failure. To address this concern, we studied the expression of c-mpl mRNA and c-Mpl protein by blasts from AML patients. In addition we examined the in vitro effect of MGDF as well as the combined effect of MGDF and granulocyte colony-stimulating factor (G-CSF) or stem cell factor (SCF) on leukemic blast proliferation, recruitment into S-phase, induction of programmed cell death and activation of signal transducers and activators of transcription (STAT) proteins. Our results demonstrate that blasts from a substantial proportion of cases of AML express the receptor at either the mRNA or protein level. Moreover, the function of the MGDF receptor was demonstrated by activation of STAT proteins following exposure to MGDF. Nevertheless, blast proliferation in response to MGDF was rare, and the proliferative effect of MGDF was less than that of G-CSF or SCF. Furthermore, MGDF did not prevent programmed cell death induced by cytarabine. Finally, there appeared to be no correlation between receptor expression by AML blasts and functional response to MGDF. Based on these data, it would appear that clinical trials of MGDF may be undertaken safely in patients with AML.

Octreotide does not prevent diarrhea in patients treated with weekly 5-fluorouracil plus high-dose leucovorin.

The somatostatin analog, octreotide, is effective in treating diarrhea associated with cancer chemotherapy. This study was undertaken to determine whether octreotide could be used as prophylaxis against chemotherapy-induced diarrhea and, thereby, permit increased dose intensity. Adult cancer patients were treated with a standard regimen of intravenous 5-fluorouracil (5-FU) (600 mg/m2) plus leucovorin (LV) (500 mg/m2) weekly x 6 weeks. In addition, 150 microg of octreotide was administered subcutaneously twice daily, beginning on the first day of chemotherapy and continuing for 43 days. Escalation of 5-FU was planned for successive cohorts based upon toxicity. Eleven patients were treated at the initial 5-FU dose level. In 10 evaluable patients, dose-limiting toxicities were diarrhea (two patients), fatigue (one patient), and hyperbilirubinemia (one patient). Diarrhea was experienced by six of 10 patients, and only three patients were able to receive six weekly chemotherapy treatments without dose reduction or delay. At a dose of 150 microg twice daily, octreotide did not prevent diarrhea associated with 5-FU plus LV, and 5-FU dose escalation was not possible. While octreotide is successful in the treatment of 5-FU-induced diarrhea, we were unable to demonstrate a role in toxicity prophylaxis.

Prospective sequential trials of induction weekly cisplatin followed by monthly cisplatin, doxorubicin, cyclophosphamide and paclitaxel and cisplatin in optimal (< or = 1 cm) stage III and IV ovarian cancer.

PURPOSE OF INVESTIGATION: This study was conduced to assess the results of paclitaxel plus cisplatin given over six months as firstline therapy in women with stage III and IV epithelial ovarian cancer with residual disease < 1 cm and compare it to our previous standard of cisplatin, adriamycin, and cyclophosphamide given over ten months in two sequential trials totaling 100 patients. METHODS: We compared induction weekly cisplatin (1 mg/kg x 4) followed by monthly cisplatin (50 mg/m2), doxorubicin (50 mg/m2) and cyclophosphamide (750 mg/m2) x 10 (n = 56) versus induction cisplatin (1 mg/kg x 4) followed by cisplatin (75 mg/m2) and paclitaxel (135 mg/m2) monthly over six months (n = 44). RESULTS: The two groups were similar in age, histologic subtypes, grade, performance status, and substage. The mean dose of cisplatin in the PAC patients was 617.1 (+/-92.7) mg/m2 as compared to 567.1 (+/-89.2) mg/m2 in the TP patients (p < 0.0001). Surgical response was assessed in 83.9% of the PAC and 86.4% of the TP patients. The incidence of nausea and vomiting, myelotoxicity and renal toxicity were similar in the two groups. Peripheral neuropathy occurred more frequently following TP (57% vs 16%; p = 0.001). Cardiac toxicity (grade 1) occurred in 39% of the PAC patients and in 4.5% of the TP patients (p < 0.001). The overall response rate (75% vs 88.7%), surgical response rate (67.9% vs 79.5%), complete surgical responses (37.5% vs 40.9%), estimated two-year survival (80.2% vs 79.6%), progression-free median survival (36 months vs 30.4 months) and two-year progression/recurrence rates (32.3% vs 46.9%), respectively, of PAC and TP patients were not statistically significant (p = NS). CONCLUSIONS: Given the discussed limitations of the study, compared with PAC, TP did not improve overall and surgical response rates, two-year survival, two year disease-free survival, or median time of recurrence in patients with optimal (< 1 cm) stage III and IV ovarian cancer and resulted in higher peripheral neuropathy rates.

Two sequential studies for primary peritoneal carcinoma: induction with weekly cisplatin followed by either cisplatin-doxorubicin-cyclophosphamide or paclitaxel-cisplatin.

OBJECTIVES: The aim of the current study is to evaluate the results of therapy with induction with weekly cisplatin followed by the combination of cisplatin-doxorubicin-cyclophosphamide (PAC) or the combination paclitaxel-cisplatin (TP) as first-line chemotherapy in patients with primary peritoneal adenocarcinoma (PPA). METHODS: Between October 1988 and July 1996, 46 patients with PPA were treated with PAC (n = 25) or TP (n = 21) following cytoreductive surgery in two sequential trials. In trial 1, patients received induction with weekly cisplatin (1 mg/kg) x 4 followed by monthly cisplatin (50 mg/m2), cyclophosphamide (750 mg/m2), and doxorubicin (50 mg/m2) for 10 cycles. In trial 2, patients received induction with weekly cisplatin (1 mg/kg) x 4 followed by monthly cisplatin (75 mg/m2) and paclitaxel (135 mg/m2) over 24 hr for 6 cycles. Surgical assessment of response was performed in 15 (60.0%) and 13 (61.9%) patients in the PAC and TP trials, respectively. Estimated survival and progression-free survival distributions were calculated by the method of Kaplan and Meier. Survival curves were compared using the log rank test. RESULTS: There were no significant differences between patients in either treatment arm with respect to median age, substage, percentage of patients undergoing optimal cytoreductive surgery, median preoperative CA125 values, performance status, proportion of patients who had second-look procedures, or median cumulative doses of cisplatin. The incidence of nausea and vomiting as well as peripheral neuropathy was significantly higher among patients who received TP (P = 0.005 and 0.022, respectively). The overall response, surgical response, and complete surgical response were not statistically different among patients who received PAC and those who received TP (62.5% versus 70.0%, P = 0.75, 73.3% versus 76.9%, P = 0.1, and 13.3% versus 23.1%, P = 0.64, respectively). Patients who underwent optimal cytoreductive surgery demonstrated higher response than patients whose tumors could not be optimally cytoreduced (76.7% versus 42.9%, P = 0.04). There was no statistically significant difference in overall survival or time to progression/recurrence between the PAC and TP groups (median 21.5 versus 24.0 months, P = 0.68, and 17.3 versus 24.0 months, P = 0.59, respectively). In both treatment groups combined, 18 of 32 patients whose tumors were optimally cytoreduced and 3 of 14 patients whose tumors were suboptimally cytoreduced had surgically verified response. Patients who underwent optimal cytoreductive surgery exhibited longer survival than those who underwent suboptimal cytoreductive surgery (median 29.4 versus 18.6 months, P = 0.008). CONCLUSIONS: Both PAC and TP regimens are effective combinations in patients with PPA. The median survival was similar following PAC and TP but the responses and time to recurrence/progression were nonsignificantly better in the paclitaxel combination.

Serum CA-125 measurements > 65 U/mL. Clinical value.

OBJECTIVE: To review the prevalence of various conditions associated with serum CA-125 values > 65 U/mL, to calculate the odds ratios of different ranges of high CA-125 in predicting cancer and to study the effect of menopause and the presence of a mass on the predictive value of high serum CA-125. STUDY DESIGN: A retrospective review of the diagnoses in 313 consecutive women seen at the Cleveland Clinic Foundation whose serum CA-125 was > 65 U/mL was performed. Statistical analysis was performed using crosstabulation, chi 2, Fisher's exact test and the odds ratio. RESULTS: In patients with serum CA-125 > 65 U/mL, gynecologic cancers, nongynecologic cancers and non-malignant conditions constituted 74.3%, 10.2% and 13.1% of diagnoses, respectively. In patients with serum CA-125 > or = 1,000 U/mL, the same conditions were responsible for 89%, 7% and 3% of diagnoses, respectively. Endometriosis and metastatic breast cancer were the most common benign condition and nongynecologic cancer associated with serum CA-125 > 65 U/mL. The presence of an abdominopelvic mass significantly increased the risk of malignancy (P < .00005). Approximately 90% of patients with CA-125 > 65 U/mL and no mass had nonmalignant disease. The diagnoses of serum CA-125 values > 65 U/mL varied significantly in premenopausal versus postmenopausal patients. Postmenopausal patients had a higher incidence of gynecologic (P = .002) and nongynecologic (P = .0008) cancers and lower incidence of benign conditions (P < .0005). The odds ratio that CA-125 levels were associated with cancer increased as the level of CA-125 increased. The odds ratio of malignant versus benign disease was significantly higher in post-menopausal patients for all intervals of CA-125 levels until the level of > or = 1,000 U/mL was reached. CONCLUSION: In patients seen at a tertiary center, serum CA-125 measurements > 65 U/mL were associated with nonmalignant conditions in 13% of patients. Although higher serum CA-125 levels were more associated with gynecologic malignancies, no level of CA-125 occurred exclusively with gynecologic cancers. In postmenopausal patients with serum CA-125 values > 65 U/mL and in patients with serum CA-125 values > 65 U/mL and an abdominopelvic mass, subspecialty consultation should be considered before proceeding to surgery.

p53 overexpression is not an independent prognostic factor for patients with primary ovarian epithelial cancer.

BACKGROUND: The clinical significance of p53 overexpression in patients with ovarian carcinoma is uncertain. Previous studies have yielded conflicting results and have been hampered by small patient populations, failure to account for other well-known prognostic variables in multivariate analysis, and failure to account for the grade of p53 overexpression. The aim of this study was to investigate the independent prognostic significance of p53 overexpression in patients with primary ovarian epithelial cancer (POEC). METHODS: Tumors obtained from 221 patients with primary ovarian epithelial cancer (POEC) (Stages I-IV) were studied for p53 overexpression semiquantitatively by immunohistochemical techniques. The median duration of follow-up of surviving patients was 7 years. The presence or absence and degree of p53 overexpression were correlated with the clinicopathologic features of the study population and overall survival. Survival curves were constructed according to the Kaplan-Meier method, and differences in survival were assessed with the log rank test. The prognostic significance of p53 overexpression for survival was assessed in a multivariate analysis with the Cox proportional hazards model. RESULTS: One hundred seven tumors (48.4%) exhibited p53 overexpression. The overexpression was graded as mild in 16.7% of cases, moderate in 5.9%, and strong in 25.8%. p53 overexpression was associated with advanced stage (P = 0.04), higher grade (P = 0.0003), serous histology (P = 0.0018), and patient age > 61 years (P = 0.013). In univariate analysis, p53 overexpression was a significant prognostic factor (P = 0.049 for any degree of overexpression, P = 0.03 for strong overexpression). However, in multivariate analysis, after adjustment for stage and size of residual tumor following cytoreductive surgery, p53 overexpression did not retain statistical significance. Survival curves for patients with different stages and grades of tumor differentiation did not demonstrate a difference in survival among patients with no p53 overexpression, compared with those who demonstrated any degree of p53 overexpression or compared with those who demonstrated strong p53 overexpression. CONCLUSIONS: p53 overexpression is not an independent prognostic factor for patients with primary ovarian epithelial cancer.

Angiogenesis and dynamic MR imaging gadolinium enhancement of malignant and benign breast lesions.

PURPOSE: To determine whether dynamic magnetic resonance (MR) imaging enhancement parameters are associated with vessel density of malignant and benign breast lesions. MATERIALS AND METHODS: Forty-five patients with 48 breast lesions underwent gadolinium-enhanced spoiled gradient-recalled echo (SPGR) MR imaging followed by excisional biopsy and Factor VIII staining and vessel density measurement in the lesions. RESULTS: The vessel densities were not significantly different in 25 malignant breast lesions as compared to 23 benign breast lesions. Among all 48 lesions, greater MR enhancement showed an association with increased vessel density. Seventy-four percent of all lesions with MRI enhancement amplitude greater or equal to three times post-precontrast ratio had vessel densities greater than the median of 172 as compared to 34% of lesions with enhancement amplitude less than three times, p = 0.02. The rate and washout of MR enhancement showed no significant association with vessel density. CONCLUSION: Although there is an overall significant association between greater MRI enhancement amplitude and vessel density, MRI gadolinium enhancement of breast lesions is not an accurate predictor of vessel density.

Age at onset of ovarian cancer in women with a strong family history of ovarian cancer.

OBJECTIVE: To determine whether women with a strong family history of ovarian cancer develop ovarian cancer at a younger age than the general population, and to determine if the age at onset of ovarian cancer in families with multiple cases of ovarian cancer is progressively younger with successive generations. METHODS: Using a large voluntary familial ovarian cancer registry, 90 probands were identified whose grandmothers had developed ovarian cancer and for whom the age at onset was known. The distribution of age at onset of ovarian cancer in the grandmothers was compared to the expected distribution based on data from the Surveillance Epidemiology End Results (SEER) project. In addition, 131 families were identified for whom complete pedigrees were available and in whom 3 or more family members had developed ovarian cancer. Ovarian cancer-free survival curves were constructed for each aggregate generation (using the probands as the reference generation) utilizing the Kaplan-Meier method. RESULTS: Among the 90 grandmothers, 18 from families with 3 or more cases of ovarian cancer had a distribution of age of onset that was younger than expected (P = 0.02). However, the distribution of age at onset among the 72 grandmothers from families with only 2 cases of ovarian cancer was not significantly different from that expected based on the SEER data (P = 0.18). Among the 131 families with 3 or more cases of ovarian cancer, the probands' daughters developed ovarian cancer at a younger age than the probands (P = 0.018), probands developed ovarian cancer at a younger age than their mothers (P = 0.0008), and the probands' mothers developed ovarian cancer at a younger age than the probands' grandmothers (P = 0.0038). CONCLUSIONS: Ovarian cancer patients from families with 3 or more cases of ovarian cancer tend to develop their cancer at a younger than expected age. This is consistent with the phenomenon known as anticipation.

Characterization of interleukin-10 receptor expression on B-cell chronic lymphocytic leukemia cells.

B-cell chronic lymphocytic leukemia (B-CLL) cells accumulate in vivo in the G0/G1 phase of the cell cycle, suggesting that their malignant expansion is due, at least in part, to a delay in cell death. However, the cellular or molecular factors responsible for a delay in B-CLL cell death are unknown. B-CLL cells do express receptors for interferon-alpha (IFN-alpha) and IFN-gamma, and activation of both has been shown to promote B-CLL survival in vitro by preventing apoptosis. The interleukin-10 (IL-10) receptor is another member of the IFN receptor family, but its ligand, IL-10, has been reported to induce apoptosis in B-CLL cells. In the current study, we undertook a biochemical analysis of IL-10 receptor expression on freshly isolated B-CLL cells and characterized the functional responsiveness of IL-10 binding to its constitutively expressed receptor. We show that B-CLL cells bind IL-10 with significant specificity and express between 47 and 127 IL-10 receptor sites per cell, with a dissociation constant in the range of 168 to 426 x 10(-12) mol/L. Ligand binding and activation of the IL-10 receptor expressed on B-CLL cells results in the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 proteins. This pattern of STAT protein phosphorylation is identical to IL-10 receptor activation on normal cells and similar to IFN-alpha (STAT1 and STAT3) and IFN-gamma (STAT1) receptor activation in CLL. Further, in consecutive samples of fresh blood obtained from patients with B-CLL cells, the addition of IL-10 inhibited B-CLL proliferation, enhanced B-CLL differentiation, but did not induce apoptosis. Indeed, IL-10, like IFN-gamma, was able to significantly reduce the amount of B-CLL cell death caused by hydrocortisone-induced apoptosis. We conclude that cytokines, which signal through the interferon family of receptors, have comparable functional effects on B-CLL cells.